Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease

Ewa Dudzińska; Kinga Szymona; Renata Kloc; Paulina Gil-Kulik; Tomasz Kocki; Małgorzata Świstowska; Jacek Bogucki; Janusz Kocki; Ewa M Urbanska

doi:10.1177/1756284819881304

Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease

Therap Adv Gastroenterol. 2019 Oct 19:12:1756284819881304. doi: 10.1177/1756284819881304. eCollection 2019.

Authors

Ewa Dudzińska¹, Kinga Szymona², Renata Kloc³, Paulina Gil-Kulik⁴, Tomasz Kocki³, Małgorzata Świstowska⁴, Jacek Bogucki⁴, Janusz Kocki⁴, Ewa M Urbanska³

Affiliations

¹ Medical University of Lublin, Chodźki 1 Street, Lublin, 20-093, Lubelskie, Poland.
² Medical University of Lublin, Lublin, Lubelskie, Poland.
³ Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Lublin, Lubelskie, Poland.
⁴ Department of Clinical Genetics, Medical University of Lublin, Lublin, Lubelskie, Poland.

Abstract

Background: Complex interaction of genetic defects with environmental factors seems to play a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Accumulating data implicate a potential role of disturbed tryptophan metabolism in IBD. Kynurenic acid (KYNA), a derivative of tryptophan (TRP) along the kynurenine (KYN) pathway, displays cytoprotective and immunomodulating properties, whereas 3-OH-KYN is a cytotoxic compound, generating free radicals.

Methods: The expression of lymphocytic mRNA encoding enzymes synthesizing KYNA (KAT I-III) and serum levels of TRP and its metabolites were evaluated in 55 patients with IBD, during remission or relapse [27 patients with ulcerative colitis (UC) and 28 patients with Crohn's disease (CD)] and in 50 control individuals.

Results: The increased expression of KAT1 and KAT3 mRNA characterized the entire cohorts of patients with UC and CD, as well as relapse-remission subsets. Expression of KAT2 mRNA was enhanced in patients with UC and in patients with CD in remission. In the entire cohorts of UC or CD, TRP levels were lower, whereas KYN, KYNA and 3-OH-KYN were not altered. When analysed in subsets of patients with UC and CD (active phase-remission), KYNA level was significantly lower during remission than relapse, yet not versus control. Functionally, in the whole groups of patients with UC or CD, the TRP/KYN ratio has been lower than control, whereas KYN/KYNA and KYNA/3-OH-KYN ratios were not altered. The ratio KYN/3-OH-KYN increased approximately two-fold among all patients with CD; furthermore, patients with CD with relapse, manifested a significantly higher KYNA/3-OH-KYN ratio than patients in remission.

Conclusion: The presented data indicate that IBD is associated with an enhanced expression of genes encoding KYNA biosynthetic enzymes in lymphocytes; however, additional mechanisms appear to influence KYNA levels. Higher metabolic conversion of serum TRP in IBD seems to be followed by the functional shift of KYN pathway towards the arm producing KYNA during exacerbation. We propose that KYNA, possibly via interaction with aryl hydrocarbon receptor or G-protein-coupled orphan receptor 35, may serve as a counter-regulatory mechanism, decreasing cytotoxicity and inflammation in IBD. Further longitudinal studies evaluating the individual dynamics of TRP and KYN pathway in patients with IBD, as well as the nature of precise mechanisms regulating KYNA synthesis, should be helpful in better understanding the processes underlying the observed changes.

Keywords: Crohn’s disease; HPLC; PCR; kynurenine pathway; ulcerative colitis.